EP1131113B1 - Protheses bioactives en materiau conducteur revetu d'un polymere et d'une substance a proprietes immunosuppressives, antistenose et antithrombose - Google Patents

Protheses bioactives en materiau conducteur revetu d'un polymere et d'une substance a proprietes immunosuppressives, antistenose et antithrombose Download PDF

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EP1131113B1
EP1131113B1 EP99972115A EP99972115A EP1131113B1 EP 1131113 B1 EP1131113 B1 EP 1131113B1 EP 99972115 A EP99972115 A EP 99972115A EP 99972115 A EP99972115 A EP 99972115A EP 1131113 B1 EP1131113 B1 EP 1131113B1
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Prior art keywords
polymer
copolymer
bioactive substance
substance
bioactive
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EP99972115A
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German (de)
English (en)
French (fr)
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EP1131113A1 (fr
Inventor
Alain Le Moel
Natacha Betz
Christophe Bureau
Guy Deniau
Charles Baquey
Gérard DELERIS
Werner Haberbosch
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Kerckhoff-Klinik GmbH
Institut National de la Sante et de la Recherche Medicale INSERM
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
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Kerckhoff-Klinik GmbH
Commissariat a lEnergie Atomique CEA
Institut National de la Sante et de la Recherche Medicale INSERM
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A61L33/0029—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate using an intermediate layer of polymer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/258—Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment

Definitions

  • the present invention relates to bioactive prostheses with particular immunosuppressive properties, antistenosis and antithrombotics.
  • Such prostheses can be used in the field of cardiology and surgery vascular as a substitute for arteries or as endocalibreurs or "stents" arranged in arteries, especially in the coronary arteries, to avoid any risk of thrombosis or restenosis.
  • Bioactive prostheses can also be used in many other areas where it is important to give the prosthesis a property addition due to the presence of a substance bioactive.
  • Implantation of coronary endocalibreurs plays an increasingly important role for the treatment of chronic coronary heart disease, but so far these endocalibreurs have not been able to solve the problem of restenosis and the rates of restenosis after implantation of the endocalibreur are still 22 to 32%. As we have just seen, this restenosis is the result of a proliferation neointimal tissue that should be prevented.
  • prostheses including endocalibreurs coronaries, which would prevent this tissue proliferation.
  • the document EP-A-596 615 [1] describes prostheses whose substrate is polymer which are covered with a layer of grafted polymer retaining an active product.
  • EP-A-0 873 732 [2] discloses a calibrator on which heparin is fixed, for example through a coating with groups Heparin-attracting functional groups obtained, for example, medium of a methane plasma and a gas plasma ammonia or amine monomer.
  • EP-A-0 832 618 [4] discloses stents with long-term anti-thrombogenicity, which comprise a metal support on which is for example fixed heparin by means of a coupling and a crosslinking agent, after oxidation of the metal surface.
  • FR-A-2 187 849 [11] has also described biocompatible and biofunctional materials of various biomedical applications in which a biological molecule is chemically bonded to a polymer or a copolymer which has been previously grafted by radiation. to an inert polymer substrate.
  • the present invention is specifically for subject of new prostheses that do not give rise to this disadvantage.
  • the subject of the invention is a bioactive prosthesis comprising a support whose surface is of a material selected from metals, metal alloys, semiconductor materials, conductive polymers, carbon fibers and their mixtures, said surface being coated with a polymer or copolymer layer with reactive functions covalently bonded to the surface of the medium, and a bioactive substance fixed on the prosthesis through said functions reactive so that it can be released gradually on a site of implantation of the prosthesis.
  • This prosthesis thus presents a additional property due to the presence of a appropriate bioactive substance to treat or prevent, directly on the implantation site of the prosthesis, the development of phenomena undesirable.
  • the surface of the support of the prosthesis is in a material that can be a metal, a metal alloy, a conductive polymer, a semiconductor material, fibers of carbon, or mixtures thereof.
  • the support can be realized in totality in one of these materials or have a soul in any type of material surrounded by a layer of one of the materials defined above.
  • Metals and metal alloys are chosen, for example, from stainless steels, alloys based on cobalt or titanium, shape-memory alloys, noble metals like gold or platinum, and alloys of noble metals.
  • Conductive polymers that can be used in the invention to form the surface of the support can to be of various types.
  • the material used to support the prosthesis is chosen mainly according to the mechanical properties that the prosthesis must present.
  • a support is advantageously used metal, for example stainless steel or metal alloy with shape memory.
  • the surface of the support of the prosthesis is coated with a layer of polymer or copolymer with reactive functions for the purpose of temporarily retain a bioactive substance which will then be released on the implantation site of the prosthesis.
  • polymer means not only a polymer-based identical monomers but also a copolymer with base of different monomers.
  • the appropriate reactive functions for this fixation can be chosen, for example, among the functions acid, ester, amide, amine and hydroxyl.
  • the polymer used to form this layer must be biocompatible.
  • polymers include polymers acrylics and methacrylics such as the polymethylmethacrylate, polymethacrylate of ethyl, polyacrylic acid, acid polymethacrylic, poly (methacrylate) hydroxyethyl) and polyacrylamide, alcohol polyvinyl, poly (4-vinylpyridine), dextran, polystyrene, conductive polymers based on thiophene, aniline, pyrrole, and everything polymer or copolymer using monomers obtained by functionalization of the above-mentioned monomers.
  • polymers are or may be provided with appropriate reagents, chosen according to the mode of fixation of the biological substance.
  • the bioactive substance can be fixed directly to the functions reactants of the polymer layer by a bond covalent with possible interposition of an arm spacer between the reactive functions and the substance.
  • the bioactive substance can also be fixed on the reactive functions of the polymer via microreservoirs containing this substance, which are fixed on the reactive functions of the layer.
  • microreservoirs may comprise a microporous outer membrane that is related to reactive functions of the polymer layer.
  • this membrane microporous may be polyacrylamide.
  • microreservoirs agarose beads directly loaded with the bioactive substance or responsible for spherulites themselves responsible for the substance bioactive.
  • the bioactive substance used is chosen according to the properties you want confer on the prosthesis.
  • This bioactive substance can belong for example to the group of compounds antimitotic, anti-aggregating, anti-inflammatory, antirestenosis, antithrombotics, immunosuppressants, anti-rejection and antibiotics.
  • oligonucleotides can play the role of decoy for mRNA and constitute targets for cell proliferation genes to various levels. In the case of cardiac prostheses, they can oppose the proliferation of cells smooth muscle.
  • the bioactive substance can be chosen especially from the cyclosporine, rapamycin, aspirin, ticlopidine, 3-deazaadenosine and MCP-1.
  • MCP-1 is a chemotactic protein for macrophages.
  • Cyclosporine is an agent immunosuppressant that inhibits factor expression tissue in stimulated monocytes and cells smooth muscle after implantation of endocalibreurs coronary.
  • Rapamycin is also an agent immunosuppressant that inhibits dependent kinases cyclin, and can be used to prevent the restenosis of the blood vessels.
  • the polymer layer can be used to retain a heparin compound by a covalent bond, which compound gives it anticoagulant, antithrombotic and anti-restenosis properties.
  • the surface of the support of a polymer and then the polymer to introduce the functions reactive.
  • the deposition of the polymer layer is done by electropolymerization using the surface of the support as deposition electrode.
  • Electropolymerization consists of polymerization of an initiated monomer. electrochemically by electronic transfer of the electrode surface to a monomer molecule or the opposite. It gives rise to the deposit of two types of polymers on the surface of the electrode, very similar chemical structures and yet easily separable, as described in: P. Dahl et al., Journal of Electroanalytical Chemistry, 470, 14 (1999) [5], in J. Charlier and al., Journal of Electroanalytical Chemistry 465, 200 (1999) [6], and in: C. Bureau et al., Journal of Adhesion, 58, 101, 1996 [7].
  • These two types of polymers are a chemically grafted polymer on the surface of the electrode, of a thickness between About 2 and 100 nm; and an ungrafted polymer, the thickness can be up to 40 ⁇ m.
  • the non polymer grafted can be removed by simply rinsing with a adequate solvent, while the graft polymer resists to rinses under ultrasounds.
  • the mechanism of polymer formation today admitted for the cathodic electropolymerization reactions is the one anionic propagation, either from the surface (graft polymer) either directly into the solution (polymer in solution), both mechanisms being connected by a bifurcation, as described in the references above and in: C. Office and al.
  • Reactive functions can be implanted on this graft polymer, either using monomers already having interesting reactive functions (groupings esters), or by carrying out the copolymerization of these monomers with monomers functionalized with functional groups possibly protected, either causing the appearance of these groupings functional by chemical treatment, electrochemical and / or subsequent radiochemical.
  • the polymer can be obtained at from anionically polymerizable monomer, chosen for example from acrylonitrile, methacrylonitrile, 4-vinyl pyridine, 4-chlorostyrene, methyl methacrylate, ethyl methacrylate, their functionalized derivatives, epoxy group monomers as well as copolymers obtained from these monomers, it is a anionic polymerization by electro-initiation cathode.
  • anionically polymerizable monomer chosen for example from acrylonitrile, methacrylonitrile, 4-vinyl pyridine, 4-chlorostyrene, methyl methacrylate, ethyl methacrylate, their functionalized derivatives, epoxy group monomers as well as copolymers obtained from these monomers, it is a anionic polymerization by electro-initiation cathode.
  • the polymer can be obtained at from a polymerizable monomer cationic, chosen for example from N-vinyl pyrrolidone, 4-vinyl pyridine, pyrrole, thiophene, aniline, or any monomer obtained by functionalization of these basic monomers, or any copolymer involving these monomers, this is a cationic polymerization by electroinitiation anodic.
  • a polymerizable monomer cationic chosen for example from N-vinyl pyrrolidone, 4-vinyl pyridine, pyrrole, thiophene, aniline, or any monomer obtained by functionalization of these basic monomers, or any copolymer involving these monomers
  • the polymer deposited by electropolymerization can constitute the polymer to reactive functions, or it can serve as a layer intermediary on which the polymer with reactive functions.
  • This second deposit can be made either by radiografting, or by plasma polymerization of a precursor monomer of the functional polymer reactive.
  • Radiografting consists of forming, under the action of ionizing radiations, reactive sites on the polymer formed by electropolymerization, from which we can initiate the polymerization of monomers. These sites are created by irradiation, by example by means of electrons, X-rays, rays gamma or accelerated heavy ion beams. The irradiation can be carried out before putting the polymer formed by electropolymerization on the support in contact with the monomer or simultaneously with this putting in contact.
  • the polymerization conditions are chosen so as to obtain a layer of polymer of appropriate thickness on the intermediate layer formed by electropolymerization on the support of the prosthesis.
  • heparin such as heparin.
  • This can be performed during radiografting of the precursor monomer of the polymer by adding heparin to the medium of grafting containing the precursor monomer to be grafted.
  • Acrylic acid can be used for this purpose as monomer precursor, to fix heparin, as it is described by Baquey et al, in "Innov. tech. Biol. Med., Vol. 2, No. 4, 1981, page 378-389 "[9].
  • the reactive functions of the polymer layer to fix a bioactive substance in such a way that it can be released then on the implantation site of the prosthesis.
  • microreservoirs or microcapsules fixed on the reactive functions of the polymer, these microreservoirs being filled with the bioactive substance and with a wall allowing release this substance over an extended period.
  • microreservoirs can be agarose microspheres directly loaded with bioactive substance, in the form of a polymeric prodrug or spherulites, themselves responsible for bioactive substance.
  • the agarose microbeads are surrounded by a microfiltration membrane, by example polyacrylamide, which has a microporosity as it allows the passage of the active substance for an extended period.
  • Agarose microspheres can be formed as follows.
  • the beads agarose loaded with the bioactive substance or spherulites by extrusion into an oily vein, and introduces the beads into a capillary where they are driven by a flow of oil, then coated by a photopolymerizable solution provided by a capillary adjacent.
  • the photopolymerizable solution may be example based on acrylamide and bis-acrylamide, and one can thus form a polyacrylamide membrane around the balls.
  • the porosity of this membrane can be controlled by adjusting the concentration of bis-acrylamide of the solution.
  • microbeads are then fixed on the polymer layer which, in this case, may comprise reactive functions of the COOH type to form amide bonds between these COOH groups and groups amine reported on the polyacrylamide membrane of microbeads.
  • These amine groups can be trained to from hexamethylene diamine which is fixed on the polyacrylamide by the coupling technique hydrazine.
  • spherulites this is lipid complexes consisting of nested layers within or between which is incorporated the bioactive substance. In the body, the release of this substance is obtained by the action endogenous lipases.
  • the fixation of spherulites on the polymer layer can be carried out also at medium of polyacrylamide by putting the spherulites into suspension in an extrudable agarose solution and gellable in oily vein in the form of marbles are subsequently circumscribed by a membrane of polyacrylamide with controllable permeability.
  • the bioactive substance is a simple molecule such as aspirin
  • the bioactive substance can be regenerated and released by hydrolysis of acetylsalicylate.
  • the hydroxyl functional polymer can be for example the poly (methacrylate hydroxyethyl), dextran or alcohol Polyvinyl.
  • the fixation of the bioactive substance on the polymer can be made after depositing the layer of polymer on the support or simultaneously with this deposit.
  • acetylsalicylic acid fixed on poly hydroxyethyl methacrylate
  • This example illustrates the realization endocalibreurs or "stents", comprising a support metal coated with poly (methyl methacrylate) (PMMA) on which are fixed spherulites CAPSULIS, which are responsible of antibiotic.
  • PMMA poly (methyl methacrylate)
  • an electrolytic cell equipped with three electrodes which are respectively a working electrode, a reference electrode and an auxiliary electrode, the system being controlled by a potentiostat connected to a computer.
  • the working electrode is constituted by the metal end-calibrator and an electrochemical solution comprising the monomer, methyl methacrylate (MMA), dissolved in a proportion of 30% by volume in a compatible solvent consisting of dimethyl sulfoxide which is added an electrolyte carrier salt consisting of tetrabutyl ammonium perchlorate or tetrabutyl ammonium tetrafluoroborate, at a concentration of 3 ⁇ 10 -2 mol / l.
  • the endocalibreur is placed as a working electrode in the electrolytic solution and the deposit is made at a potential of -2.6 volts (Ag + / Ag), that is to say with respect to a silver electrode as an electrode.
  • the mechanism of polymerization is an anionic mechanism that takes place in solution and on the surface.
  • the polymer that forms in solution is washed away, while the polymer on the surface is chemically grafted onto the S surface of the electrode.
  • the antibiotic-laden spherulites are then suspended at a concentration of 15% by volume in a photopolymerizable solution comprising from 15 to 20% by weight of acrylamide and 5% by weight of bis-acrylamide, the remainder being constituted by the solvent, the water in this case containing 10 -5 M riboplasmin (photoinitiator) and 10 -3 M N, N'-tetramethylene ethylene diamine TEMED (reducing agents).
  • a photopolymerizable solution comprising from 15 to 20% by weight of acrylamide and 5% by weight of bis-acrylamide, the remainder being constituted by the solvent, the water in this case containing 10 -5 M riboplasmin (photoinitiator) and 10 -3 M N, N'-tetramethylene ethylene diamine TEMED (reducing agents).
  • the association of balls is realized polyacrylamide on the support coated with polymethyl methacrylate, after having hydrolysed the polymethacrylate so that it has functions COOH reagents.
  • covalent bonds are formed between amine groups brought on polyacrylamide by coupling with hexamethylene diamine, and the acid polymethacrylic acid resulting from the hydrolysis of PMMA, which secures the spherulites and the antibiotic substance on the polymer layer.
  • a poly (4-vinylpyridine) metal end-scaler is overlaid with heparin.
  • heparin a poly (4-vinylpyridine) metal end-scaler
  • An electrochemical cell is used to three electrodes as before, in which the working electrode is constituted by the stainless steel (316L) stapler.
  • the working electrode is constituted by the stainless steel (316L) stapler.
  • a poly (4-vinylpyridine) film having a thickness of 100 nanometers is thus obtained.
  • This film is then modified by fixing on it heparin.
  • the PMMA-coated metal endoscarriers on which the polyacrylic acid is grafted are then extracted, the amount of which is evaluated by titration of the -COOH functions (some 10 -9 moles per mm 2 ).
  • This example illustrates the realization of a PMMA-coated metal stainer as in Example 1 and a layer of poly (methacrylate) of hydroxyethyl) on which is fixed aspirin (acetylsalicylic acid).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Materials Engineering (AREA)
  • Biomedical Technology (AREA)
  • Surgery (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP99972115A 1998-11-16 1999-11-15 Protheses bioactives en materiau conducteur revetu d'un polymere et d'une substance a proprietes immunosuppressives, antistenose et antithrombose Expired - Lifetime EP1131113B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9814351A FR2785812B1 (fr) 1998-11-16 1998-11-16 Protheses bioactives, notamment a proprietes immunosuppressives, antistenose et antithrombose, et leur fabrication
FR9814351 1998-11-16
PCT/FR1999/002795 WO2000029043A1 (fr) 1998-11-16 1999-11-15 Protheses bioactives a proprietes immunosuppressives, antistenose et antithrombose

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EP1131113A1 EP1131113A1 (fr) 2001-09-12
EP1131113B1 true EP1131113B1 (fr) 2005-07-20

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US11622871B2 (en) 2015-06-05 2023-04-11 W. L. Gore & Associates, Inc. Low bleed implantable prosthesis with a taper

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US8029563B2 (en) 2004-11-29 2011-10-04 Gore Enterprise Holdings, Inc. Implantable devices with reduced needle puncture site leakage
US8906087B2 (en) 2004-11-29 2014-12-09 W. L. Gore & Associates, Inc. Method of making implantable devices with reduced needle puncture site leakage
US9814560B2 (en) 2013-12-05 2017-11-14 W. L. Gore & Associates, Inc. Tapered implantable device and methods for making such devices
US11259910B2 (en) 2013-12-05 2022-03-01 W. L. Gore & Associates, Inc. Tapered implantable device and methods for making such devices
US11622871B2 (en) 2015-06-05 2023-04-11 W. L. Gore & Associates, Inc. Low bleed implantable prosthesis with a taper

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WO2000029043A1 (fr) 2000-05-25
EP1131113A1 (fr) 2001-09-12
PT1131113E (pt) 2005-11-30
JP2002529203A (ja) 2002-09-10
FR2785812B1 (fr) 2002-11-29
DE69926255T2 (de) 2006-04-20
MXPA01004898A (es) 2007-08-21
ATE299719T1 (de) 2005-08-15
CA2349930A1 (fr) 2000-05-25
JP4294873B2 (ja) 2009-07-15
AU769176B2 (en) 2004-01-15
CA2349930C (fr) 2007-06-26
DE69926255D1 (de) 2005-08-25
IL143086A0 (en) 2002-04-21
US6517858B1 (en) 2003-02-11
DK1131113T3 (da) 2005-11-14
FR2785812A1 (fr) 2000-05-19
ES2246592T3 (es) 2006-02-16
IL143086A (en) 2006-08-20
AU1168100A (en) 2000-06-05

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